Serum levels of S-100 protein are directly proportional to the size, number, thickness and degree of cellularity of congenital melanocytic nevi
Authors: Alejandra Tomás-Velázquez, Juan Carlos López-Gutiérrez, Miguel Reyes-Múgica, Claudia M. Salgado, Sandra Hervás-Stubbs, Carlos de Andrea, Dipanjan Basu, Eva M. Andrés, Paloma Triana, Carmen Ceballos, Gabriel Reina, Pedro Redondo
Journal: Journal of the American Academy of Dermatology (2023)

To the Editor: Some patients with congenital melanocytic nevi (CMN) present progressive growth and thickening, extracutaneous involvement (neurocutaneous melanocytosis, NCM) or neoplastic transformation (melanoma); and others remain stable or even regress. There are no markers to assess progression or follow-up. Recently, we found S-100, a protein which acts on cell differentiation and proliferation, elevated in CMN.1Tomas-Velazquez A. Lopez-Gutierrez J.C. Ceballos C. et al.S-100B serum protein is elevated in children with medium-to-giant congenital melanocytic nevi: an exploratory case-control study.J Am Acad Dermatol. 2020; 83: 222-224Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar S-100 is a ligand of the RAGE pathway (related to the MAPK-pathway), and low serum levels of soluble-RAGE were related to poor survival in melanoma.2Wagner N.B. Weide B. Reith M. et al.Diminished levels of the soluble form of RAGE are related to poor survival in malignant melanoma.Int J Cancer. 2015; 137: 2607-2617Crossref Scopus (27) Google Scholar Also SOX10, expressed in melanocytes with high specificity, is useful in detection, prognosis and treatment assessment of melanoma.3Blokzijl A. Chen L.E. Gustafsdottir S.M. et al.Elevated levels of SOX10 in serum from Vitiligo and melanoma patients, analyzed by proximity ligation assay.PLoS One. 2016; 11e0154214Crossref Scopus (5) Google Scholar We explored if S-100, RAGE and SOX10 serum levels vary in children's CMN and assessed clinical or pathological correlations. This prospective, case-control, multicenter study enrolled consecutive patients with medium-to-giant-CMNs who underwent surgery (April 2019-December 2020). Left over serum samples of sex-and-age-matched healthy controls (HC) and a small group of metastatic melanoma patients were collected. The study was approved by the University Clinic of Navarra institutional review board and participants provided informed consent. CMN categorization was performed according to Krengel et al4Krengel S. Scope A. Dusza S.W. et al.New recommendations for the categorization of cutaneous features of congenital melanocytic nevi.J Am Acad Dermatol. 2013; 68: 441-451Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar criteria. S-100 was determined with an electrochemiluminescence-immunoassay; RAGE and SOX10 with ELISA kits. Representative tissue specimens taken during certain patients' surgery were analyzed for nevomelanocytic extent and proliferation. Supplementary Material, available via Mendeley at https://data.mendeley.com/datasets/mzr3rvxdkh/1. 64 CMN (Table I), 64 HC and 10 metastatic melanoma patients were recruited. CMN presented the highest levels of S-100; and lower levels of RAGE and higher levels of SOX10 than HC (Fig 1). Serial analyses were performed in 11 CMN showing that S-100 and SOX10 tended to decrease (correlation S-100-SOX10 Rho 0.253, P = .362) while RAGE increased (correlation S-100-RAGE Rho −0.432, P = .107) across time and treatments (months between determinations: median 21, 7-36). S-100 showed association with size, satellite nevi, hypertrichosis and subcutaneous tissue alterations (Table I and Supplementary Fig 2, available via Mendeley at https://data.mendeley.com/datasets/mzr3rvxdkh/1), and multivariate analysis showed that extensive dermal nodules, >20 satellites, or at least notable hypertrichosis increased S-100 values (coefficients 0.35, P = .011; .34, P = .008; and .20, P = .041). Higher serum levels of S-100 and SOX10 correlated with higher Melan-A+ and S-100+deep dermis areas; and S-100 serum levels correlated with S-100+subcutaneous-areas (Table I). Serum SOX10 and subcutaneous Ki67+ presented positive correlation (Rho 0.438 P = .029) and serum RAGE presented negative correlation with lesion thickness (Rho −0.62 P = .001).Table ICharacteristics of CMN patients and lesions and clinical and histopathological correlation with serum protein levelsPatients (N = 64)S-100 (μg/L): mean (IQR)P valueAge, median (IQR)9 (5-12)Male, n (%)21 (32.81)Neurocutaneous melanosis, n (%).843 No56 (87.5)0.31 (0.13-0.55) Yes8 (12.5)0.27 (0.14-0.46)Subcutaneous tissue alteration, n (%).042 No55 (85.9)0.19 (0.10-0.38) Yes9 (14.1)0.35 (0.19-0.71)Size classification depending on PAS n (%).030 M1 1.5-10 cm11 (17.19)0.09 (0.05-0.14) M2 >10-20 cm8 (12.50)0.19 (0.14-0.45) L1 >20-30 cm11 (17.19)0.31 (0.16-0.58) L2 >30-40 cm5 (7.81)0.31 (0.11-0.71) G1 >40-60 cm12 (18.75)0.17 (0.08-0.51) G2 >60 cm17 (26.56)0.31 (0.19-0.43)No. of satellite nevi n (%).039 No satellites23 (35.94)0.14 (0.09-0.25) <20 satellites14 (21.88)0.28 (0.12-0.52) 20-50 satellites11 (17.19)0.49 (0.15-1.35) >50 satellites16 (25.00)0.31 (0.19-0.46)Dermal or subcutaneous nodules n (%).087 None41 (64.06)0.19 (0.10-0.32) Scattered14 (21.88)0.27 (0.14-0.52) Extensive9 (14.06)0.53 (0.19-1.21)Hypertrichosis n (%).043 None8 (12.50)0.09 (0.05-0.19) Notable25 (39.06)0.27 (0.11-0.75) Marked31 (48.44)0.22 (0.15-0.49)General location #n (%).588 Head25 (39.06)0.16 (0.09-0.32) Trunk10 (15.63)0.26 (0.09-0.76) Extremities7 (10.94)0.15 (0.13-0.78) Head + trunk4 (6.25)0.22 (0.09-1.08) Trunk + extremities16 (25.00)0.32 (0.16-0.50) Head + trunk + extremities2 (3.13)0.38 (0.22-0.53)Histopathological analysis (N = 25)Melanocyte extentSerum proteinRhoP valueDeep dermisMelan-AS-1000.41.043SOX100.64<.001RAGE0.18.384S-100S-1000.44.028SOX100.58.002RAGE−0.17.421Subcutaneous tissueMelan-AS-1000.34.107SOX100.29.170RAGE−0.20.334S-100S-1000.61.001SOX100.38.080RAGE−0.06.765Bold P-values indicate statistically significant results; bold S-100 levels and IQR in clinical features indicate the subgroups significantly different.Regarding histopathological analysis, Melan-A+ and S-100+ areas and the number of Ki-67+ cells were studied using ImageJ software in dermis and with conventional semi-quantitative scales in subcutaneous tissue. In addition to results presented in the table, a positive correlation between serum SOX10 and subcutaneous Ki67+ (Rho 0.438 P = .029) and a negative correlation between serum RAGE and lesion thickness (Rho −0.62 P = .001) were found. Supplementary Methods Material, available via Mendeley at https://data.mendeley.com/datasets/mzr3rvxdkh/1.CMN, Congenital melanocytic nevus; G1 and G2, giant; IQR, interquartile range; L1 and L2, large; M1 and M2, medium; PAS, projected adult size. Open table in a new tab Bold P-values indicate statistically significant results; bold S-100 levels and IQR in clinical features indicate the subgroups significantly different. Regarding histopathological analysis, Melan-A+ and S-100+ areas and the number of Ki-67+ cells were studied using ImageJ software in dermis and with conventional semi-quantitative scales in subcutaneous tissue. In addition to results presented in the table, a positive correlation between serum SOX10 and subcutaneous Ki67+ (Rho 0.438 P = .029) and a negative correlation between serum RAGE and lesion thickness (Rho −0.62 P = .001) were found. Supplementary Methods Material, available via Mendeley at https://data.mendeley.com/datasets/mzr3rvxdkh/1. CMN, Congenital melanocytic nevus; G1 and G2, giant; IQR, interquartile range; L1 and L2, large; M1 and M2, medium; PAS, projected adult size. Findings indicate higher nevomelanocytes populations result in greater S-100 release into the blood, as patients with larger, multiple, deeper and more cellular lesions presented higher levels. CMNs' size and satellites were reported to correlate with melanoma and NCM though no definitive conclusions could be made in regard to these complications in the present study due to sample size. However, it seems plausible that in those children affected by CMN suffering overgrowth, melanoma, or NCM progression, serial determinations of serum S-100 could help in early detection and treatment, being complementary to physical examination and MRI. Usefulness of serum S-100 in melanoma, even within normal ranges, was highlighted recently.5Ertekin S.S. Podlipnik S. Ribero S. et al.Monthly changes in serum levels of S100B protein as a predictor of metastasis development in high-risk melanoma patients.J Eur Acad Dermatol Venereol. 2020; 34: 1482-1488Crossref Scopus (7) Google Scholar Long-term studies are needed to understand serum proteins variations across time in different settings. S-100 could be an easy, noninvasive, affordable analysis in CMN characterization and follow-up. We are grateful to our patients and relatives for their cooperation and kindness and to all the colleagues who helped us with the study. None disclosed.